Since the CRF2 receptor was cloned in 1995, relatively little has been learned about its functional biology due primarily to the lack of pharmacological tools. Anatomical distribution data had suggested that the CRF2 receptor could be involved in feeding behaviors, which led to the idea that an antagonist to this receptor could have utility in treating eating disorders like anorexia nervosa. Recently, however, a selective peptide antagonist (antisauvagine-30) and agonist (urocortin II) have become available. Preliminary data obtained with antisauvagine-30 and urocortin II verified the importance of the CRF2 receptor in anorectic behavior, but the antisauvagine-30 (ASV-30) data also suggested that the CRF2 receptor may be involved in emotional behavior and anxiety. Thus, the potential therapeutic market for a CRF2 receptor antagonist could include a much broader spectrum of emotional disorders than anorexia nervosa. Therefore, we have proposed to investigate the possibility that the CRF2 receptor plays a role in anxious behavior, using ASV-30 and urocortin II as pharmacological tools. In anticipation of a positive finding, we have also proposed to begin the process of identifying a selective, high affinity, orally available CRF2 antagonist that could be used not only for the treatment of anorexia nervosa, but also for the treatment of anxiety disorders. Therefore, Phase I is focused: 1) on biological proof of principle for the role of CRF2 receptors in anxiety, and 2) on the initial identification of a high affinity CRF2 antagonist. Phase II would follow up with the actual development of such an antagonist, fine-tuning for selectivity, oral bioavailability and safety. PROPOSED COMMERCIAL APPLICATION: A small molecule CRF2 receptor antagonist could represent an anti?anxiety therapeutic with a novel mechanism of action and the potential to provide an improved efficacy and side effect profile in comparison to available therapeutics. Anxiety disorders are the most common form of mental illness in the United States, with an estimated one year prevalence of 16.4%, and an estimated cost of $993/year/person (USDHHS, et al., 1999).